The research underlying the following technology was supported by NIH Grants CA 36622 and CA 50750.
1. Field of the Invention
This invention relates to the isolation of naamidine A from sea sponges and methods for its use as an inhibitor of tumor growth. In particular, the present invention relates to the use of naamidine A extracted from sea sponges to inhibit the growth of cancerous tumors, including skin cancer tumors, that are dependent upon epidermal growth factor ("EGF") for their growth.
2. Relevant Technology
A. Cancer.
Cancer is one of the most feared diseases and has claimed the lives of millions of people. Although the list of known cancer-causing agents is long, the exact causes of most cancers remain relatively unknown. However, it is known that cancer is the uncontrolled proliferation of malignant cells, which proliferation causes the progressive destruction of normal body tissue and functions and, eventually, death. This process can be slow or rapid depending on the location or nature of the cancerous tissue.
Considerable research and resources have been devoted to finding useful antitumor treatments. While methods and compositions have been developed which aid in inhibiting, remitting, or controlling the growth of tumors, new and better methods in antitumor chemical compositions are needed.
The elusive goal of most cancer treatments has been to stop the proliferation of the cancerous cells through the prohibition of cell regeneration without, at the same time, disrupting normal cell activity necessary to sustain life. This is most often attempted through the use of antineoplastic agents which interfere with the replication of the deoxyribonucleic acid ("DNA"), cause damage to the DNA, or disrupt the mitotic progression of the cancer cells.
Typical cancer treatments can generally be divided into one of the following categories: (1) antineoplastic agents, (2) hormones and steroids, (3) antiemetics, (4) anti-infectives, (5) narcotics, (6) nonnarcotic analgesics, and (7) tranquilizers. Only the first group (and to a certain extent, the second group) of treatments actually inhibits the growth of cancerous cells, while the other six serve mainly to reduce pain or relieve some of the other symptoms experienced by the cancer victim.
All of these various anticancer agents have been used with varying degrees of success. However, they all share the disadvantage that treatments that inhibit cell growth in cancerous cells extends to normal cells as well and can lead to serious and potentially life threatening side effects. Therefore, new anticancer treatments are continuously being sought which will prove to be more selective in inhibiting cancer cells, while being less toxic to the normal cells.
B. Isolation of Antitumor Agents from Marine Life.
Plants and animals have yielded a number of chemical molecules which have useful biological activity, including antitumor activity. One particularly rich source of biologically active chemicals are marine organisms, which comprise over half a million species. Marine organisms have been found to produce a variety of metabolic substances which often have unprecedented chemical structures because of their unusual living environment as compared with terrestrial organisms.
In recent years, an increasing number of natural products extracted from marine organisms have been reported to exhibit a variety of biological activities such as antimicrobial, antiviral, antifungal and anticancer activities. These include peptides, polyethers, alkaloids, prostanoids, and the like. The marine life forms that are known to have yielded useful compounds include sponges, octocorals, algae, tunicates, nuclibranches, bryozoans and marine bacteria.
Already patents have been obtained for a number of compounds extracted from marine life that have exhibited antitumor activity. U.S. Pat. No. 4,729,996 discloses antitumor compounds with imidazole rings, which were isolated from the marine sponges Teichaxinella morchella and Ptioocaulis walpersi. U.S. Pat. No. 4,808,590 discloses nitrogen containing cyclic compounds isolated from the marine sponge Theoneloa sp. which have antiviral, antitumor and antifungal properties. U.S. Pat. No. 4,866,084 discloses bisindole alkaloids extracted from the marine sponge Spongosorites ruetzleri useful in treating certain classes of tumors. U.S. Pat. No. 4,970,226 discloses bis-indole imidazole alkaloids and derivatives isolated from the marine sponge Spongosorites sp. which exhibit useful antitumor and antimicrobial properties.
In addition to these patents, a number of publications disclose biologically useful organic compounds derived from marine sponges, including Scheuer, P. J. (ed.) Marine Natural Products, Chemical and Biological Perspectives Academic Press, New York, 1978-1983, Vol. I-V; Faulkner, D. J., 1984 Natural Products Reports 1:551-598; Natural Products Reports 1986 3:1-33; Natural Products Reports 1987 4:539-576; Natural Products Reports 1988 5:613-663; J. Am. Chem. c. 1985 107:4796-4798.
C. The Isolation of Naamidine A from Marine Sponges.
Naamidine A was first isolated by Shmuel Carmely and Yoel Kasman in 1987 from the red sea sponge Leucetta chagosensis. See Carmely, S., et al., Naamines and Naamidines, Novel Imidazole Alkaloids From the Calcareous Sponge, Tetrahedron Lett., Vol. 28, No. 26, pp. 3003-06 (1987). A structurally similar molecule, isonaamidine B, was isolated from the same sponge by Shmuel Carmely, Micha Ilan and Yoel Kashman in 1989. See Carmely, S., et al., 2-Amino Imidazole Alkaloids From the Marine Sponge Leucetta chagosensis, Tetrahedron Lett., Vol. 45, No. 7, pp. 2193-2200 (1989).
Although isolated and reported, naamidine A was not known to possess any useful biological activities prior to the efforts of the present inventors. As reported in the publications listed above, this compound was merely identified in terms of its chemical structures, physical properties, and spectral characteristics. Thus, before the efforts of the present inventors this compound was unknown as a potential pharmaceutical agent. Nevertheless, because naamidine A has been isolated and characterized and is readily available it would be a significant advancement in the art relative to naamidine A if it were proved to possess biologically important properties.
In general, it will be appreciated that it would be an advancement in the art if naturally occurring compounds could be found which had antitumor properties. It would be an even more profound advancement in the art if such naturally occurring compounds exhibited selectivity such that they would inhibit the growth of cancerous cells without unduly inhibiting the growth or activity of normal cells such that they would not result in the death of the organism being treated.
Finally, it would be an advancement in the art if naamidine A could be used to selectively inhibit the growth of cancerous cells without unduly inhibiting the growth or activity of normal tissue cells.
Such teachings and methods are disclosed and claimed herein.